chr8-144424956-C-A

Variant names:

• chr8-144424956-C-A
• rs781982468
• NM_016208.4:c.290G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016208.4(VPS28):​c.290G>T​(p.Arg97Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,420,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R97C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VPS28 NM_016208.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.81
• Publications: 3 publications found

Genes affected

VPS28 (HGNC:18178): (VPS28 subunit of ESCRT-I) This gene encodes a protein subunit of the ESCRT-I complex (endosomal complexes required for transport), which functions in the transport and sorting of proteins into subcellular vesicles. This complex can also be hijacked to facilitate the budding of enveloped viruses from the cell membrane. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016208.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS28	NM_016208.4	MANE Select	c.290G>T	p.Arg97Leu	missense	Exon 6 of 10	NP_057292.1	Q548N1
	VPS28	NM_183057.3		c.290G>T	p.Arg97Leu	missense	Exon 6 of 9	NP_898880.1	Q9UK41-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS28	ENST00000292510.6	TSL:1 MANE Select	c.290G>T	p.Arg97Leu	missense	Exon 6 of 10	ENSP00000292510.3	Q9UK41-1
	VPS28	ENST00000377348.6	TSL:1	c.290G>T	p.Arg97Leu	missense	Exon 6 of 9	ENSP00000366565.2	Q9UK41-2
	VPS28	ENST00000526054.5	TSL:1	c.290G>T	p.Arg97Leu	missense	Exon 5 of 9	ENSP00000434064.1	Q9UK41-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 181816 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1420670 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 703198

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32574

American (AMR) AF: 0.00 AC: 0 AN: 37446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25394

East Asian (EAS) AF: 0.00 AC: 0 AN: 37596

South Asian (SAS) AF: 0.00 AC: 0 AN: 82190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090196

Other (OTH) AF: 0.00 AC: 0 AN: 58872

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.039	D
Polyphen		0.76	P
Vest4		0.63
MutPred		0.46		Gain of catalytic residue at R97 (P = 0.0072)
MVP		0.21
MPC		0.33
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.88
gMVP		0.75
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781982468; hg19: chr8-145650339;